CA1267416A - 1,4-dihydropyridine derivatives useful for the treatment of cardiovascular disorders - Google Patents

1,4-dihydropyridine derivatives useful for the treatment of cardiovascular disorders

Info

Publication number: CA1267416A
Authority: CA; Canada
Prior art keywords: methyl; compound; phenyl; cyano; dihydro
Prior art date: 1985-06-17
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Fee Related

Application number

CA000510582A

Other languages

English (en)

French (fr)

Inventor

Ila Sircar

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Warner Lambert Co LLC

Original Assignee

Warner Lambert Co LLC

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1985-06-17

Filing date

1986-06-02

Publication date

1990-04-03

1986-06-02 Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC

1990-04-03 Application granted granted Critical

1990-04-03 Publication of CA1267416A publication Critical patent/CA1267416A/en

2007-04-03 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

Links

YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title abstract description 8
208000024172 Cardiovascular disease Diseases 0.000 title abstract description 6
150000001875 compounds Chemical class 0.000 claims abstract description 169
PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 156
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 149
ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims description 88
125000004494 ethyl ester group Chemical group 0.000 claims description 80
229960003512 nicotinic acid Drugs 0.000 claims description 79
235000001968 nicotinic acid Nutrition 0.000 claims description 79
239000011664 nicotinic acid Substances 0.000 claims description 79
-1 nitro, amino Chemical group 0.000 claims description 78
125000000217 alkyl group Chemical group 0.000 claims description 67
125000001309 chloro group Chemical group Cl* 0.000 claims description 49
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 45
125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 38
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 29
125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 27
229910052739 hydrogen Inorganic materials 0.000 claims description 23
239000001257 hydrogen Substances 0.000 claims description 23
MPFLRYZEEAQMLQ-UHFFFAOYSA-N dinicotinic acid Chemical group OC(=O)C1=CN=CC(C(O)=O)=C1 MPFLRYZEEAQMLQ-UHFFFAOYSA-N 0.000 claims description 22
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 22
125000004093 cyano group Chemical group *C#N 0.000 claims description 21
238000000034 method Methods 0.000 claims description 16
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 15
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
125000003545 alkoxy group Chemical group 0.000 claims description 13
DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical group C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 claims description 13
125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 13
125000004001 thioalkyl group Chemical group 0.000 claims description 13
239000000203 mixture Substances 0.000 claims description 12
150000003839 salts Chemical class 0.000 claims description 10
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 9
125000003277 amino group Chemical group 0.000 claims description 8
125000003710 aryl alkyl group Chemical group 0.000 claims description 8
125000000753 cycloalkyl group Chemical group 0.000 claims description 8
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 7
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 7
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 6
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
125000001072 heteroaryl group Chemical group 0.000 claims description 6
150000002431 hydrogen Chemical class 0.000 claims description 6
RMHQDKYZXJVCME-UHFFFAOYSA-N 2-pyridin-4-ylpyridine Chemical compound N1=CC=CC=C1C1=CC=NC=C1 RMHQDKYZXJVCME-UHFFFAOYSA-N 0.000 claims description 5
125000002947 alkylene group Chemical group 0.000 claims description 5
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 4
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
150000004702 methyl esters Chemical class 0.000 claims description 3
229910052757 nitrogen Inorganic materials 0.000 claims description 3
238000002360 preparation method Methods 0.000 claims description 3
125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
ZNQWPJOLIYWZQK-UHFFFAOYSA-N 4-pyridin-3-ylpyridine-3,5-dicarboxylic acid Chemical group OC(=O)C1=CN=CC(C(O)=O)=C1C1=CC=CN=C1 ZNQWPJOLIYWZQK-UHFFFAOYSA-N 0.000 claims description 2
150000001204 N-oxides Chemical class 0.000 claims description 2
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 2
239000003960 organic solvent Substances 0.000 claims description 2
239000011593 sulfur Substances 0.000 claims description 2
229910052717 sulfur Inorganic materials 0.000 claims description 2
125000000627 niacin group Chemical group 0.000 claims 16
125000001475 halogen functional group Chemical group 0.000 claims 8
PZQSQRCNMZGWFT-QXMHVHEDSA-N propan-2-yl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC(C)C PZQSQRCNMZGWFT-QXMHVHEDSA-N 0.000 claims 3
YTEIHWVCQJZNEN-UHFFFAOYSA-N 3-pyridin-4-ylpyridine Chemical compound C1=CN=CC(C=2C=CN=CC=2)=C1 YTEIHWVCQJZNEN-UHFFFAOYSA-N 0.000 claims 1
CHPOWWXTMZVCJS-UHFFFAOYSA-N 5-cyano-6-methyl-2-(pyridin-2-ylsulfonylmethyl)-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylic acid Chemical compound N1C(C)=C(C#N)C(C=2C(=CC=CC=2)C(F)(F)F)C(C(O)=O)=C1CS(=O)(=O)C1=CC=CC=N1 CHPOWWXTMZVCJS-UHFFFAOYSA-N 0.000 claims 1
UUGIZHLZSQXWIM-UHFFFAOYSA-N 5-cyano-6-methyl-2-[(1-methylimidazol-2-yl)sulfinylmethyl]-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylic acid Chemical group N1C(C)=C(C#N)C(C=2C(=CC=CC=2)C(F)(F)F)C(C(O)=O)=C1CS(=O)C1=NC=CN1C UUGIZHLZSQXWIM-UHFFFAOYSA-N 0.000 claims 1
230000002152 alkylating effect Effects 0.000 claims 1
SUQGDEQDNJUIEA-UHFFFAOYSA-N ethyl 2-(benzenesulfinylmethyl)-5-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate Chemical group N1C(C)=C(C#N)C(C=2C=C(C=CC=2)[N+]([O-])=O)C(C(=O)OCC)=C1C[S+]([O-])C1=CC=CC=C1 SUQGDEQDNJUIEA-UHFFFAOYSA-N 0.000 claims 1
YVEYARLKSWBQHO-UHFFFAOYSA-N ethyl 2-(benzenesulfonylmethyl)-5-cyano-6-methyl-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate Chemical compound N1C(C)=C(C#N)C(C=2C(=CC=CC=2)C(F)(F)F)C(C(=O)OCC)=C1CS(=O)(=O)C1=CC=CC=C1 YVEYARLKSWBQHO-UHFFFAOYSA-N 0.000 claims 1
ZXSIKWQCKZLXGV-UHFFFAOYSA-N ethyl 4-(2-chlorophenyl)-5-cyano-6-methyl-2-(phenylsulfanylmethyl)-1,4-dihydropyridine-3-carboxylate Chemical group N1C(C)=C(C#N)C(C=2C(=CC=CC=2)Cl)C(C(=O)OCC)=C1CSC1=CC=CC=C1 ZXSIKWQCKZLXGV-UHFFFAOYSA-N 0.000 claims 1
PDCBOHCSILNBMZ-UHFFFAOYSA-N ethyl 4-(2-chlorophenyl)-5-cyano-6-methyl-2-(pyridin-4-ylsulfinylmethyl)-1,4-dihydropyridine-3-carboxylate Chemical group N1C(C)=C(C#N)C(C=2C(=CC=CC=2)Cl)C(C(=O)OCC)=C1CS(=O)C1=CC=NC=C1 PDCBOHCSILNBMZ-UHFFFAOYSA-N 0.000 claims 1
KSCPPGOYQPYVOP-UHFFFAOYSA-N ethyl 5-cyano-2-[(4-methoxyphenyl)sulfinylmethyl]-6-methyl-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate Chemical group N1C(C)=C(C#N)C(C=2C(=CC=CC=2)C(F)(F)F)C(C(=O)OCC)=C1CS(=O)C1=CC=C(OC)C=C1 KSCPPGOYQPYVOP-UHFFFAOYSA-N 0.000 claims 1
SPKMPSMHSFMFSU-UHFFFAOYSA-N ethyl 5-cyano-6-methyl-2-(pyridin-4-ylsulfanylmethyl)-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate Chemical group N1C(C)=C(C#N)C(C=2C(=CC=CC=2)C(F)(F)F)C(C(=O)OCC)=C1CSC1=CC=NC=C1 SPKMPSMHSFMFSU-UHFFFAOYSA-N 0.000 claims 1
DWWKCSMTDQKEPS-UHFFFAOYSA-N ethyl 5-cyano-6-methyl-2-(pyridin-4-ylsulfinylmethyl)-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate Chemical group N1C(C)=C(C#N)C(C=2C(=CC=CC=2)C(F)(F)F)C(C(=O)OCC)=C1CS(=O)C1=CC=NC=C1 DWWKCSMTDQKEPS-UHFFFAOYSA-N 0.000 claims 1
ZUAWKQNJMCYABQ-UHFFFAOYSA-N ethyl 5-cyano-6-methyl-2-(pyridin-4-ylsulfonylmethyl)-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate Chemical compound N1C(C)=C(C#N)C(C=2C(=CC=CC=2)C(F)(F)F)C(C(=O)OCC)=C1CS(=O)(=O)C1=CC=NC=C1 ZUAWKQNJMCYABQ-UHFFFAOYSA-N 0.000 claims 1
KECACFCAOSUFCO-UHFFFAOYSA-N ethyl 5-cyano-6-methyl-2-[(2-methylphenyl)sulfinylmethyl]-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate Chemical group N1C(C)=C(C#N)C(C=2C(=CC=CC=2)C(F)(F)F)C(C(=O)OCC)=C1CS(=O)C1=CC=CC=C1C KECACFCAOSUFCO-UHFFFAOYSA-N 0.000 claims 1
230000001706 oxygenating effect Effects 0.000 claims 1
DCBSHORRWZKAKO-UHFFFAOYSA-N rac-1-monomyristoylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(O)CO DCBSHORRWZKAKO-UHFFFAOYSA-N 0.000 claims 1
230000000694 effects Effects 0.000 abstract description 9
230000000297 inotrophic effect Effects 0.000 abstract description 8
230000002107 myocardial effect Effects 0.000 abstract description 6
229940127291 Calcium channel antagonist Drugs 0.000 abstract description 5
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract description 3
239000011575 calcium Substances 0.000 abstract description 3
229910052791 calcium Inorganic materials 0.000 abstract description 3
230000009090 positive inotropic effect Effects 0.000 abstract description 3
230000009286 beneficial effect Effects 0.000 abstract description 2
230000008485 antagonism Effects 0.000 abstract 1
239000002253 acid Substances 0.000 description 18
239000000243 solution Substances 0.000 description 12
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 10
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
150000007513 acids Chemical class 0.000 description 6
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
241000124008 Mammalia Species 0.000 description 5
238000004587 chromatography analysis Methods 0.000 description 5
125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 5
150000002148 esters Chemical class 0.000 description 5
239000011541 reaction mixture Substances 0.000 description 5
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239000000480 calcium channel blocker Substances 0.000 description 4
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208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
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ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
238000006243 chemical reaction Methods 0.000 description 3
GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 3
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SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 3
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JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
229940030600 antihypertensive agent Drugs 0.000 description 2
239000002220 antihypertensive agent Substances 0.000 description 2
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
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125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
238000013375 chromatographic separation Methods 0.000 description 2
230000000875 corresponding effect Effects 0.000 description 2
CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 2
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UUWFZYVIKAOUAP-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine-3,5-dicarboxylic acid Chemical class OC(=O)C1CNC=C(C(O)=O)C1 UUWFZYVIKAOUAP-UHFFFAOYSA-N 0.000 description 1
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229940124345 antianginal agent Drugs 0.000 description 1
239000003416 antiarrhythmic agent Substances 0.000 description 1
210000000709 aorta Anatomy 0.000 description 1
230000001746 atrial effect Effects 0.000 description 1
SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
229940077388 benzenesulfonate Drugs 0.000 description 1
SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
229940092714 benzenesulfonic acid Drugs 0.000 description 1
125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
230000001588 bifunctional effect Effects 0.000 description 1
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
125000004432 carbon atom Chemical group C* 0.000 description 1
150000001722 carbon compounds Chemical class 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
150000001735 carboxylic acids Chemical class 0.000 description 1
239000000496 cardiotonic agent Substances 0.000 description 1
230000003177 cardiotonic effect Effects 0.000 description 1
230000005792 cardiovascular activity Effects 0.000 description 1
239000002327 cardiovascular agent Substances 0.000 description 1
229940125692 cardiovascular agent Drugs 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
229910052801 chlorine Inorganic materials 0.000 description 1
125000000068 chlorophenyl group Chemical group 0.000 description 1
125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
229940000425 combination drug Drugs 0.000 description 1
230000000295 complement effect Effects 0.000 description 1
230000009989 contractile response Effects 0.000 description 1
208000029078 coronary artery disease Diseases 0.000 description 1
210000004351 coronary vessel Anatomy 0.000 description 1
239000012043 crude product Substances 0.000 description 1
230000007423 decrease Effects 0.000 description 1
239000008121 dextrose Substances 0.000 description 1
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
238000004821 distillation Methods 0.000 description 1
230000002526 effect on cardiovascular system Effects 0.000 description 1
239000003480 eluent Substances 0.000 description 1
239000012259 ether extract Substances 0.000 description 1
ODTNEXFBAKHBBR-UHFFFAOYSA-N ethyl 2-(benzenesulfonylmethyl)-5-cyano-6-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylate Chemical compound N1C(C)=C(C#N)C(C=2C=CC=CC=2)C(C(=O)OCC)=C1CS(=O)(=O)C1=CC=CC=C1 ODTNEXFBAKHBBR-UHFFFAOYSA-N 0.000 description 1
LLGOMIPFKKCDSD-UHFFFAOYSA-N ethyl 3-oxo-4-phenylsulfanylbutanoate Chemical compound CCOC(=O)CC(=O)CSC1=CC=CC=C1 LLGOMIPFKKCDSD-UHFFFAOYSA-N 0.000 description 1
WAAZDCWPYLRFLI-UHFFFAOYSA-N ethyl 5-cyano-6-methyl-2-[(2-methylphenyl)sulfanylmethyl]-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate Chemical compound N1C(C)=C(C#N)C(C=2C(=CC=CC=2)C(F)(F)F)C(C(=O)OCC)=C1CSC1=CC=CC=C1C WAAZDCWPYLRFLI-UHFFFAOYSA-N 0.000 description 1
230000001747 exhibiting effect Effects 0.000 description 1
239000000284 extract Substances 0.000 description 1
238000000605 extraction Methods 0.000 description 1
239000000706 filtrate Substances 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
125000002541 furyl group Chemical group 0.000 description 1
150000002367 halogens Chemical group 0.000 description 1
239000012433 hydrogen halide Substances 0.000 description 1
229910000039 hydrogen halide Inorganic materials 0.000 description 1
125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
125000001041 indolyl group Chemical group 0.000 description 1
229910052500 inorganic mineral Inorganic materials 0.000 description 1
239000000543 intermediate Substances 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
LVPMIMZXDYBCDF-UHFFFAOYSA-N isocinchomeronic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)N=C1 LVPMIMZXDYBCDF-UHFFFAOYSA-N 0.000 description 1
238000002955 isolation Methods 0.000 description 1
125000005956 isoquinolyl group Chemical group 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000010755 mineral Nutrition 0.000 description 1
239000011707 mineral Substances 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
208000031225 myocardial ischemia Diseases 0.000 description 1
210000004165 myocardium Anatomy 0.000 description 1
KYTZHLUVELPASH-UHFFFAOYSA-N naphthalene-1,2-dicarboxylic acid Chemical compound C1=CC=CC2=C(C(O)=O)C(C(=O)O)=CC=C21 KYTZHLUVELPASH-UHFFFAOYSA-N 0.000 description 1
YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical class C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
PVNIIMVLHYAWGP-UHFFFAOYSA-M nicotinate Chemical compound [O-]C(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-M 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
239000004533 oil dispersion Substances 0.000 description 1
239000011368 organic material Substances 0.000 description 1
125000002971 oxazolyl group Chemical group 0.000 description 1
230000010412 perfusion Effects 0.000 description 1
SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
125000003373 pyrazinyl group Chemical group 0.000 description 1
125000003226 pyrazolyl group Chemical group 0.000 description 1
125000001725 pyrenyl group Chemical group 0.000 description 1
125000002098 pyridazinyl group Chemical group 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
GJAWHXHKYYXBSV-UHFFFAOYSA-N pyridinedicarboxylic acid Natural products OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 1
125000004076 pyridyl group Chemical group 0.000 description 1
125000000714 pyrimidinyl group Chemical group 0.000 description 1
125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
125000005493 quinolyl group Chemical group 0.000 description 1
125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
238000010992 reflux Methods 0.000 description 1
230000004044 response Effects 0.000 description 1
102200155797 rs28933378 Human genes 0.000 description 1
239000012266 salt solution Substances 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
210000002460 smooth muscle Anatomy 0.000 description 1
239000011734 sodium Substances 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
229910000104 sodium hydride Inorganic materials 0.000 description 1
229910000162 sodium phosphate Inorganic materials 0.000 description 1
239000007787 solid Substances 0.000 description 1
239000007858 starting material Substances 0.000 description 1
230000004936 stimulating effect Effects 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
239000000126 substance Substances 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
150000003457 sulfones Chemical class 0.000 description 1
150000003462 sulfoxides Chemical class 0.000 description 1
239000000725 suspension Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
125000000335 thiazolyl group Chemical group 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
150000003568 thioethers Chemical class 0.000 description 1
229960000716 tonics Drugs 0.000 description 1
125000001425 triazolyl group Chemical group 0.000 description 1
230000002792 vascular Effects 0.000 description 1
229940124549 vasodilator Drugs 0.000 description 1
239000003071 vasodilator agent Substances 0.000 description 1
238000005303 weighing Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/82—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Hydrogenated Pyridines (AREA)

CA000510582A 1985-06-17 1986-06-02 1,4-dihydropyridine derivatives useful for the treatment of cardiovascular disorders Expired - Fee Related CA1267416A (en)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date
US74596585A	1985-06-17	1985-06-17
US745,965		1985-06-17
US85273186A	1986-04-21	1986-04-21
US852,731		1986-04-21

Publications (1)

Publication Number	Publication Date
CA1267416A true CA1267416A (en)	1990-04-03

Family

ID=27114542

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA000510582A Expired - Fee Related CA1267416A (en)	1985-06-17	1986-06-02	1,4-dihydropyridine derivatives useful for the treatment of cardiovascular disorders

Country Status (12)

Country	Link
EP (1)	EP0206747B1 (da)
KR (1)	KR900005024B1 (da)
AU (1)	AU601946B2 (da)
CA (1)	CA1267416A (da)
DE (1)	DE3675271D1 (da)
DK (1)	DK281186A (da)
ES (1)	ES8800904A1 (da)
FI (1)	FI862343A7 (da)
GR (1)	GR861529B (da)
NO (1)	NO862390L (da)
NZ (1)	NZ216555A (da)
PT (1)	PT82766A (da)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB8601382D0 (en) *	1986-01-21	1986-02-26	Pfizer Ltd	Dihydropyridine antiischaemic & antihypertensive agents
GB8526411D0 (en) *	1985-10-25	1985-11-27	Pfizer Ltd	Dihydropyridines
IT1197012B (it) *	1986-07-29	1988-11-25	Boehringer Biochemia Srl	2-(aciltio) metil diidropiridine, un processo per la loro preparazione e composizioni farmaceutiche che le contengono
IT1213555B (it) *	1986-12-11	1989-12-20	Boehringer Biochemia Srl	2 metiltiometildiidropiridine, un processo per laloro preparazione e composizioni farmaceutiche che le contengono.
IT1215381B (it) *	1987-03-12	1990-02-08	Boehringer Biochemia Srl	Farmaceutiche che le contengono. carbonil- e solfonil- derivati di 2-(aminoalchiltio)metil-1,4-diidropiridine, un metodo per la loro preparazione e composizioni
DE3732380A1 (de) *	1987-09-25	1989-04-06	Bayer Ag	Dihydropyridinether, verfahren zu ihrer herstellung und ihre verwendung
SE8705150D0 (sv) *	1987-12-23	1987-12-23	Haessle Ab	Novel antiarrhythmic agents

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE2239815C2 (de)	1972-08-12	1983-02-10	Bayer Ag, 5090 Leverkusen	2-Alkylamino-dihydropyridine, Verfahren zu ihrer Herstellung sowie diese enthaltende Arzneimittel
DE2242786A1 (de)	1972-08-31	1974-03-14	Bayer Ag	Verfahren zur herstellung von neuen 2-amino-1,4-dihydropyridinen mit einer carbonylfunktion sowie ihre verwendung als arzneimittel
DE2248150A1 (de)	1972-09-30	1974-04-04	Bayer Ag	Dihydropyridinpolyester, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
DE2335466A1 (de)	1973-07-12	1975-01-30	Bayer Ag	Alkoxyalkyl-1,4-dihydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
BE843576A (fr)	1975-04-03	1976-12-29		Derives de 1,4-dihydropyridine et leur procede de preparation
GB1591089A (en)	1976-12-17	1981-06-10	Fujisawa Pharmaceutical Co	1,4-dihydropyridine derivatives and process for preparation thereof
DE2658183A1 (de)	1976-12-22	1978-07-06	Bayer Ag	In 2-position substituierte 1,4- dihydropyridin-derivate, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
NZ201395A (en) *	1981-07-30	1987-02-20	Bayer Ag	Pharmaceutical compositions containing 1,4-dihydropyridines and certain of these dihydropyridines
DE3130041A1 (de)	1981-07-30	1983-02-17	Bayer Ag, 5090 Leverkusen	Dihydropyridine mit positiv inotroper wirkung, neue verbindungen, ihre verwendung in arzneimitteln und verfahren zu ihrer herstellung
DE3239273A1 (de)	1982-10-23	1984-04-26	Bayer Ag, 5090 Leverkusen	Tetrahydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung in arzneimitteln
EP0125803A3 (en) *	1983-04-27	1987-01-21	FISONS plc	Pharmaceutically active dihydropyridines
GR851819B (da) *	1984-08-17	1985-11-26	Wyeth John & Brother Ltd
EP0200524A3 (en) *	1985-05-03	1987-06-16	Pfizer Limited	Dihydropyridine calcium antagonists

1986
- 1986-06-02 CA CA000510582A patent/CA1267416A/en not_active Expired - Fee Related
- 1986-06-02 FI FI862343A patent/FI862343A7/fi not_active Application Discontinuation
- 1986-06-04 AU AU58428/86A patent/AU601946B2/en not_active Expired - Fee Related
- 1986-06-12 GR GR861529A patent/GR861529B/el unknown
- 1986-06-16 NO NO862390A patent/NO862390L/no unknown
- 1986-06-16 KR KR1019860004759A patent/KR900005024B1/ko not_active Expired
- 1986-06-16 ES ES556082A patent/ES8800904A1/es not_active Expired
- 1986-06-16 DK DK281186A patent/DK281186A/da not_active Application Discontinuation
- 1986-06-16 NZ NZ216555A patent/NZ216555A/xx unknown
- 1986-06-16 PT PT82766A patent/PT82766A/pt unknown
- 1986-06-17 DE DE8686304679T patent/DE3675271D1/de not_active Expired - Fee Related
- 1986-06-17 EP EP86304679A patent/EP0206747B1/en not_active Expired - Lifetime

Also Published As

Publication number	Publication date
ES8800904A1 (es)	1987-12-01
EP0206747A3 (en)	1987-08-19
DK281186D0 (da)	1986-06-16
PT82766A (en)	1986-07-01
KR900005024B1 (ko)	1990-07-18
KR870000298A (ko)	1987-02-17
EP0206747A2 (en)	1986-12-30
NZ216555A (en)	1989-01-06
EP0206747B1 (en)	1990-10-31
FI862343A7 (fi)	1986-12-18
AU601946B2 (en)	1990-09-27
GR861529B (en)	1986-10-14
DK281186A (da)	1986-12-18
ES556082A0 (es)	1987-12-01
FI862343A0 (fi)	1986-06-02
NO862390L (no)	1986-12-18
DE3675271D1 (de)	1990-12-06
AU5842886A (en)	1986-12-24
NO862390D0 (no)	1986-06-16

Legal Events

Date	Code	Title	Description
1992-10-05	MKLA	Lapsed

Publication	Publication Date	Title
EP0060674B1 (en)	1985-09-18	Dihydropyridine anti-ischaemic and antihypertensive agents, processes for their production, and pharmaceutical compositions containing them
KR890001566B1 (ko)	1989-05-08	디하이드로 피리딘의 제조방법
KR880002357B1 (ko)	1988-10-29	디히드로피리딘 유도체의 제조방법
CA1105934A (en)	1981-07-28	1,4-dihydropyridine derivatives substituted in the 2- position by an alkylthioalkyl, acyloxyalkyl or phthalimidoalkyl radical
FI90543B (fi)	1993-11-15	Menetelmä lääkeaineina käyttökelpoisten dihydropyridiinin johdannaisten valmistamiseksi
US4755512A (en)	1988-07-05	Pharmaceutically useful dihydropyridinyldicarboxylate amides and esters incorporating arylpiperazinylalkyl moities
US4994461A (en)	1991-02-19	1,4-dihydropyridine enantiomers
US5068337A (en)	1991-11-26	1,4-dihydropyridines and their ability to inhibit blood platelet aggregation, inhibit thromboxane synthetase and phospholipase
PL140573B1 (en)	1987-05-30	Method of obtaining new dihydropyridine derivatives
CA1267416A (en)	1990-04-03	1,4-dihydropyridine derivatives useful for the treatment of cardiovascular disorders
IE51267B1 (en)	1986-11-26	1,4-dihydropyridine compounds having different substituents in the 2-position and 6-position,their production,and their medicinal use
CS271486B2 (en)	1990-10-12	Method of new dihydropyridinamides production
EP0257616B1 (en)	1992-10-28	Dihydropyridine derivates and pharmaceutical composition thereof
EP0215250B1 (en)	1992-12-30	2-substituted-1,4-dihydropyridines, method for their preparation and pharmaceutical compositions containing them
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